This invention relates to pharmaceutical compositions containing onosialoganglioside GM1 or a derivative thereof suitable for the treatment of Parkinson""s disease.
Parkinson""s disease is a neurodegenerative disease, which has a high rate of incidence (20 persons in 100,000 in the U.S.A.) and generally affects people older than 45-years.
Parkinson""s disease is characterized by a dopaminergic deficit, which brings about a series of neuronal events resulting in akinesia, muscle rigidity, and tremors.
Symptomatology is believed to manifest itself with the loss of at least 85% of the striatal dopaminergic innervation, consequent to the degeneration of the neurons producing DA (dopamine) in the substantia nigra and pars compacta (Kish S. J. et al., The New England J. of Med:, 318, 876, 1988).
It is to be stressed that although pharmacological therapy for Parkinson""s disease has been studied for over 25 years, the disease is still a critical problem especially due to the slow and progressive degeneration of the dopaminergic system (McGeer P. L. et al., Ann. Neurol., 24, 574, 1988).
As known, the therapy based on L-dopa, associated with peripheral decarboxylase inhibitors (carbidopa or benserazide) , with monamine oxidase inhibitors (Shoulson I. et al.: xe2x80x9cEffect of Deprenyl on the progression of disability in early Parkinson""s diseasexe2x80x9d, The New England J. of Med., 16, 1364-1371, 1989), as well as the therapy based on long-acting direct dopaminergic agonists (pergolide, cabergoline), in the great majority of early-stage cases considerably improves the clinical picture and, in some cases, provides a total control of symptoms. However, after some years treatment, i.e. from 2-3 years min. to generally 10 years max. or even more, symptomsxe2x80x94mainly characterized clinically by fluctuation and dyskinesias of various typesxe2x80x94appear anew in most patients (80-90%).
Said motor fluctuations (in particular on-off phenomena) and hyperkinesias deeply upset the patient who, after years of well-being resulting from the disease being compensated by the therapy, relapses into a decompensated condition that prevents him/her from enjoying an adequate family, social, and work life.
With a view to solving the main problem to be faced by Parkinson""s disease therapy, i.e. the decompensated phase, present clinical practice uses slow-release compositions based on levodopa associated with benserazide or carbidopa, long-acting direct dopaminergic agonists (pergolide, cabergoline), as well as infusion methods (lisuride and apomorphine subcutaneous infusion). However, no therapy has so far proved to be effective in slowing down or stopping the progression of the disorder, which is at the base of all complications occurring in the advanced phase of the disease.
As known, L-dopa and its hydroxylated metabolite (TOPA) may produce neurotoxic effects and worsen the disabling neurodegenerative pathology progression (Only J. W. et al.: xe2x80x9cExcitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson""s and Huntington""s diseasesxe2x80x9d, Exp. Neurol., 108, 268-272, 1990; Rosenberg P. A. et al.: xe2x80x9c2,4,5-Trihydroxyphenylalanine in solution forms a non-N-methyl-D-aspartate glutamatergic agonist and neurotoxinxe2x80x9d, Proc. Natl. Acad. Sci. USA, 88, 4865-4869, 1991; Newcomer T. A. et al.: xe2x80x9cDetection of TOPA (6-OH-DOPA) and TOPA quinone by HPLC reveals a spontaneous DOPA to TOPA conversion in aqueous solutionsxe2x80x9d. Excitatory Amino Acids: Excito-toxicity I p. 83).
With a view to developing new pharmacological treatments capable of modifying the evolution of Parkinson""s disease, by slowing down or inhibiting the progression of same, several experimental investigations on animals were carried out, especially aimed at identifying the neurobiological mechanisms that in parkinsonism cause cell death, in particular the death of substantia nigral cells.
Of great importance is the information obtained by using methylphenyltetrahydropyridine (MPTP), a toxic substance capable of producing a neuropathologic and neuropharmacological picture very similar to that of Parkinson""s disease (Langston J. W.: xe2x80x9cMPTP and Parkinson""s diseasexe2x80x9d, Trends in Neurosciences, 8, 2, 79-83, 1985). MPTP neurotoxicity was attributed to its oxidation, catalysed by monamine oxidase B, to the ionic species MPP+, which is actively taken up by dopaminergic cell terminals and has a inhibitory effect on the mitochondrial oxidation of NADH-dependent substrates. This results in a loss of the substantia nigra and pars compacta dopaminergic neurons as well as of the striatum-innervating dopaminergic fibres, with consequent biochemical and behavioural deficiencies.
It is also known that gangliosides, i.e. the complex sialoglycosphingolipids that are present in neuronal membranes (Ando S.: xe2x80x9cGangliosides in the nervous systemxe2x80x9d, Neuroch. Int., 5, 507-537, 1983) improve the neurologic course in the CNS of several experimental models of acute damage. On the basis of said results, GM1 was clinically applied to treat cerebral ischemic stroke (U.S. Pat. No. 4,940,694 dated Jul. 10th, 1990; Argentino C. et al.: xe2x80x9cGM1 ganglioside therapy in acute ischemic strokexe2x80x9d, Stroke, 20, 1143-1149, 1989) and traumatic spinal cord injury (patent application PD 91 000234 dated Dec. 23rd, 1991; Geisler F. H.: xe2x80x9cRecovery of motor function after spinal-cord injuryxe2x80x94a randomized placebo-controlled trial with GM1 gangliosidexe2x80x9d, The New England J. of Med., 324, 1829-1838, 1991).
The inner ester derivative of GM1 (AGF2) and the low-dose and fast-acting therapeutic efficacy of same, especially in acute ischemia models, is also known (Cahn R. et al.: xe2x80x9cInfluence of monosialoganglioside inner ester on neurologic recovery after global cerebral ischemia in monkeysxe2x80x9d, Stroke 20, 652-656, 1989).
Furthermore, the pharmacokinetic advantages offered by GM1 ester derivatives over their precursor, GM1, have already been described (Bellato P. et al.: xe2x80x9cDisposition of exogenous tritium labelled GM1 lactone in the ratxe2x80x9d, Neurochem., pp. 1-6, 1991; EP patent 85401291.1).
It has surprisingly been found that the compounds selected out of the group consisting of monosialoganglioside (GM1), its inner ester derivative (AGF2), its methyl ester (AGF4) and N-dicholoroacetyl lyso GM1 can be successfully applied to chronic Parkinson""s disease treatment for preventing or reversing the neuronal degeneration induced by a long-term L-DOPA treatment.
In fact said compounds produce a neutralizing effect on the neurotoxicity of L-Dopa metabolites such as TOPA.
Therefore, the present invention is referred to the use of the claimed compounds for the preparation of pharmaceutical compositions active in Parkinson""s disease treatment and to the relevant therapeutic method.